Pathogen-specific antigen presentation pathways to induce protective mait cell response

The National Institute of Allergy and Infectious Diseases (NIAID), a component of the Department of Health and Human Services National Institutes of Health, awarded $824,278 to Texas Biomedical Research Institute on August 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) for Project Grant R01AI201766.

The award funds comparative investigation of bacterial antigen presentation mechanisms in Mycobacterium tuberculosis and Francisella tularensis infections to identify metabolite antigens capable of inducing protective mucosal-associated invariant T (MAIT) cell responses. MAIT cells, an innate-like T cell population abundant at mucosal surfaces, recognize non-peptidic metabolite antigens presented by MR1 (major histocompatibility complex-related protein 1) and mount rapid immune responses against bacterial infections. The research seeks to resolve which metabolite antigens activate MAIT cells protectively and how different bacterial infection routes—endosomal for M.tb and cytosolic for F. tularensis—mediate antigen loading for differential MAIT cell protection. Current knowledge gaps prevent therapeutic design of effective antigenic metabolites delivered via appropriate pathways for MAIT cell-directed protection against these bacterial pathogens.

Texas Biomedical Research Institute, doing business as Southwest Foundation for Biomedical Research, is a non-profit research organization headquartered in San Antonio, Texas and hosts the Southwest National Primate Research Center. The institute operates as a prime recipient on federal infectious disease research and vaccine development grants, with substantial experience in non-human primate models and laboratory studies.

Performance occurs in San Antonio, Texas 78227, with a period of performance from August 1, 2026, through July 31, 2031.

Abstract

Mucosal-associated invariant T (MAIT) cells emerge as promising innate-like protectors against bacterial infections caused by mycobacterium tuberculosis (M.TB) and francisella tularensis (F.tularensis). Unlike conventional T cells, MAIT cells are activated by non-peptidic metabolite antigens presented by a non- polymorphic molecule called MR1 (major histocompatibility complex-related protein 1) to elicit rapid immune responses against bacterial infections. M.TB infects over a quarter of the world's population, leading to millions of deaths annually, while F.tularensis causes fatal zoonotic infections, as transmitted by various environmental vectors. MAIT cells, an abundant innate-like T cell population at the first line of host defenses, differentially protect against the lung infections caused by M.TB and F.tularensis. Although a potent metabolite antigen to activate MAIT cells has been identified, this ribityluracil antigen derived from a bacterial riboflavin precursor has been unable to sufficiently inhibit bacterial growth in animals. IT remains unknown which metabolite antigens are able to induce protective MAIT cell responses and how different bacterial infections mediate metabolite antigen loading for differential MAIT cell protection. Currently, this fundamental knowledge is missing, thus unable to support therapeutic design for delivering an effective antigenic metabolite via an appropriate pathway to induce MAIT cell-directed protection against bacterial infections. To solve these critical unknowns, we propose to comparatively investigate bacterial antigen presentation mechanisms in M.TB and F.tularensis infections to achieve functional and structural understandings of MR1 antigen presentation. M.TB and F.tularensis infect host cells differently, typically endosomal infection by M.TB and cytosol infection by F.tularensis, providing an ideal comparative model to study metatolite antigen loading in different subcellular compartments. Beyond our previous studies on MAIT cell activation mechanisms and metabolite profiles loaded to antigen-presenting molecules, we propose to test the central hypothesis that bacterial-infected cellular compartments mediate MR1 loading of specific metabolite antigens to induce differential anti-bacterial MAIT cell responses. We will elucidate the impact of bacterial-infected cellular compartments, such as endocytic and secretory pathways, on bacterial metabolite loading to MR1 protein for MAIT cell activation in M.TB and F.tularensis infections (aim 1). Moreover, we will apply our established functional metabolomic and interactomic platforms to profile and identify the structures of bacterial metabolites loaded to MR1 protein via endocytic and secretory pathways differentially to elicit anti-bacterial MAIT cell responses (aim 2). The identified novel bacterial metabolites will be chemically purified or synthesized to be functionally tested using human macrophages, lung tissues, and mice in this study. Upon completion, we will yield the knowledge of metabolite antigen presentation compartments and bacterial metabolite antigen structures to induce protective anti-bacterial MAIT cell responses against M.TB and F.tularensis infections for future translational studies and host-directed therapeutic design.